Emerging Treatments and Technologies

O R I G I N A L A R T I C L E

XENical in the Prevention of Diabetes in

Obese Subjects (XENDOS) Study
A randomized study of orlistat as an adjunct to lifestyle changes for the
prevention of type 2 diabetes in obese patients
JARL S. TORGERSON, MD, PHD1 MARK N. BOLDRIN, MS2 with type 2 diabetes are either overweight
JONATHAN HAUPTMAN, MD2 LARS SJÖSTRÖM MD, PHD1 or obese (5). The World Health Organi-
zation has estimated that the number of
adults with diabetes will more than dou-
OBJECTIVE — It is well established that the risk of developing type 2 diabetes is closely ble from an estimated 143 million in 1997
linked to the presence and duration of overweight and obesity. A reduction in the incidence of to 300 million by 2025 (5).
type 2 diabetes with lifestyle changes has previously been demonstrated. We hypothesized that The Swedish Obese Subjects (SOS)
adding a weight-reducing agent to lifestyle changes may lead to an even greater decrease in body
weight, and thus the incidence of type 2 diabetes, in obese patients.
study has demonstrated that large weight
losses in obese patients are associated
RESEARCH DESIGN AND METHODS — In a 4-year, double-blind, prospective study, with an 80% reduction in the 8-year inci-
we randomized 3,305 patients to lifestyle changes plus either orlistat 120 mg or placebo, three dence of diabetes (6). The Finnish Diabe-
times daily. Participants had a BMI ⱖ30 kg/m2 and normal (79%) or impaired (21%) glucose tes Prevention Study (DPS) and the
tolerance (IGT). Primary endpoints were time to onset of type 2 diabetes and change in body Diabetes Prevention Program (DPP) have
weight. Analyses were by intention to treat. also demonstrated that modest weight
loss achieved by lifestyle changes (diet
RESULTS — Of orlistat-treated patients, 52% completed treatment compared with 34% of and exercise) can significantly reduce the
placebo recipients (P ⬍ 0.0001). After 4 years’ treatment, the cumulative incidence of diabetes risk of developing type 2 diabetes in obese
was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P ⫽
0.0032). Exploratory analyses indicated that the preventive effect was explained by the differ-
patients with impaired glucose tolerance
ence in subjects with IGT. Mean weight loss after 4 years was significantly greater with orlistat (IGT) (7,8). A retrospective analysis of
(5.8 vs. 3.0 kg with placebo; P ⬍ 0.001) and similar between orlistat recipients with impaired obese patients with IGT receiving orlistat
(5.7 kg) or normal glucose tolerance (NGT) (5.8 kg) at baseline. A second analysis in which the treatment has shown that this weight loss
baseline weights of subjects who dropped out of the study was carried forward also demonstrated agent may also be effective in reducing the
greater weight loss in the orlistat group (3.6 vs. 1.4 kg; P ⬍ 0.001). progression to type 2 diabetes (9).
The prospective XENDOS (XENical
CONCLUSIONS — Compared with lifestyle changes alone, orlistat plus lifestyle changes in the prevention of Diabetes in Obese
resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced Subjects) study was primarily conducted
greater weight loss in a clinically representative obese population. Difference in diabetes inci- to determine the long-term effect of orl-
dence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT and
or NGT.
istat, a gastrointestinal lipase inhibitor, in
combination with lifestyle changes in re-
Diabetes Care 27:155–161, 2004 ducing progression to type 2 diabetes and
body weight over 4 years in obese, non-
diabetic patients who had either normal
glucose tolerance (NGT) or IGT. Second-

O
besity is a serious health concern studies (2– 4) show that the risk of devel-
ary aims were to determine the effect of
affecting ⬎300 million people oping type 2 diabetes is closely linked to
orlistat treatment on weight-related met-
worldwide, representing a 50% in- the presence and duration of overweight
abolic abnormalities associated with in-
crease in only 7 years (1). A number of and obesity. Indeed, ⬃90% of individuals
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
creased risk for cardiovascular disease
and the safety and tolerability of orlistat
From the 1Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Göteborg,
Sweden; and 2Hoffmann-La Roche, Nutley, New Jersey.
over 4 years.
Address correspondence and reprint requests to Professor Lars Sjöström, Department of Body Composi-
tion and Metabolism, Vita Stråket 15, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: RESEARCH DESIGN AND
lars.sjostrom@medfak.gu.se. METHODS — XENDOS was a 4-year,
Received for publication 30 May 2003 and accepted in revised form 10 October 2003.
L.S. had full access to study data and is responsible for the decision to submit.
double-blind, randomized, placebo-
All authors participated in drafting the manuscript of this article. controlled prospective study carried out
Abbreviations: BLCF, baseline observation carried forward; DPP, Diabetes Prevention Program; DPS, at 22 Swedish medical centers between
Diabetes Prevention Study; IGT, impaired glucose tolerance; ITT, intention to treat; LOCF, last observation 1997 and 2002. Details of the study de-
carried forward; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; XENDOS, XENical in the sign and the system for centralized patient
prevention of Diabetes in Obese Subjects.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion recruitment and scheduling of patients
factors for many substances. and staff at the centers have been de-
© 2004 by the American Diabetes Association. scribed previously (10). The study proto-

DIABETES CARE, VOLUME 27, NUMBER 1, JANUARY 2004 155

Orlistat and diabetes prevention
col was approved by all relevant ethics
review committees in Sweden and was
conducted in accordance with the Decla-
ration of Helsinki. All study subjects gave
written informed consent.
Participants
Eligible patients were 30 – 60 years of age,
with a BMI ⱖ30 kg/m2. Patients were re-
quired to have nondiabetic glucose toler-
ance as assessed by a 75-g oral glucose
tolerance test (OGTT) performed at base-
line using venous whole blood and the
1994 World Health Organization criteria
(2-h whole blood glucose ⬍10.0 mmol/l
and fasting whole blood glucose ⬍6.7
mmol/l) (11). Patients with IGT were also
eligible for inclusion, and the criteria for
IGT were fasting whole blood glucose
⬍6.7 mmol/l and 2-h whole blood glu-
cose 6.7–10.0 mmol/l (11). (These crite-
ria for IGT correspond to fasting venous
plasma glucose ⬍7.8 mmol/l and 2-h
plasma glucose 7.8 –11.1 mmol/l [11].)
Exclusion criteria included diabetes
and ongoing and active cardiovascular
and gastrointestinal disease and are de-
scribed in detail elsewhere (10).
After screening, eligible patients were
randomized according to sex and OGTT
results to receive either placebo or orlistat
in a one-to-one ratio, using a centralized
randomization procedure and schedule.
Blinding was ensured by use of matching
placebo and orlistat capsules. The inves-
tigators received sealed envelopes for
each patient that contained the identity of
the study medication.
Treatment regimen
During the entire study period, all pa-
tients were prescribed a reduced-calorie
diet (⬃800 kcal/day deficit) containing
30% of calories from fat and not more
than 300 mg of cholesterol per day. The
prescribed energy intake was readjusted
every 6 months to account for any weight
lost during the preceding months. Partic-
ipants received dietary counseling every 2
weeks for the first 6 months and monthly
thereafter. Patients were also encouraged
to walk at least 1 extra kilometer a day in
addition to their usual physical activity.
All patients kept physical activity diaries.
Patients were randomized to orlistat
120 mg or placebo t.i.d. with breakfast,
lunch, and dinner. Compliance was de-
termined by counting the number of cap-
sules returned by the patients at clinic
156
visits and comparing the estimated per-
centage used against that dispensed.
Assessments
A 75-g OGTT was performed at baseline
and then at every 6 months. Diagnosis of
type 2 diabetes was based on a single 2-h
whole blood glucose measure ⱖ10
mmol/l. After the first 6 months of the
study, by a protocol amendment, patients
with a diabetic OGTT underwent a repeat
OGTT within 4 weeks. A repeat positive
test was based on a 2-h whole blood glu-
cose ⱖ10 mmol/l, a whole blood fasting
glucose ⱖ6.7 mmol/l, or two consecutive
fasting whole blood glucose measure-
ments ⱖ6.7 mmol/l. Patients diagnosed
with type 2 diabetes remained in the study
and had fasting whole blood glucose levels
measured at 6-month intervals.
Body weight was recorded at every
study visit (every 3 months). Waist cir-
cumference was assessed at baseline,
months 3 and 6, and every 6 months
thereafter. Waist circumference was mea-
sured halfway between the lower rib mar-
gin and the iliac crest in the recumbent
position after a normal expiration.
Standard clinical laboratory parame-
ters, as well as plasma levels of the fat-
soluble vitamins (vitamin A [retinol],
1,25-hydroxyvitamin D, 25-hydroxyvita-
min D, vitamin E [␣-tocopherol], and vi-
tamin K1), were assessed every 6 months.
Fasting blood samples were obtained be-
fore taking study medication and were an-
alyzed by a central laboratory (Nova
Medical Medi-Lab, Copenhagen, Den-
mark). Energy intake was estimated with
a validated self-administered food ques-
tionnaire (12).
Outcome measures
The primary outcome measures were
time to onset of type 2 diabetes and
change in body weight after 4 years’ treat-
ment. Exploratory subgroup analyses of
these variables were also conducted for
patients with IGT or NGT at baseline.
Secondary efficacy variables included
change from baseline in anthropometric
measurements, metabolic profile, and (in
baseline NGT subjects) time to onset of IGT.
Statistical analysis
Based on a literature survey and previous
experience, the hazard ratio for the onset
of type 2 diabetes was assumed to be two-
to-one for placebo-to-orlistat. Therefore,
a two-sided log-rank test would require a
DIABETES CARE, VOLUME 27, NUMBER 1, JANUARY 2004
minimum of ⬃95 primary cases of type 2
diabetes in both study groups combined
to have 90% power of detecting a signifi-
cant outcome at ␣ ⫽ 0.05. With this
event-based design, 3,305 patients were
randomized and followed until sufficient
events occurred. As a consequence of the
design, study power would be unaffected
by dropout rate.
The intent-to-treat (ITT) population,
used for the primary end point of time to
onset of type 2 diabetes, consisted of all
randomized patients who received at least
one dose of study drug and had at least
one follow-up efficacy assessment. Based
on the ITT population, cumulative inci-
dence rates of type 2 diabetes were calcu-
lated using a Kaplan-Meier estimate-of-
survival function with partitions at
6-month intervals (the interval at which
OGTTs were conducted). Because OGTT
measurements were taken less frequently
than body weight measurements (the first
OGTT after randomization was taken at
week 24), fewer patients were included in
the ITT analyses of diabetes than of
weight loss. The safety population con-
sisted of all patients who received at least
one dose of orlistat with a safety follow-up.
Statistical significance of differences
between treatment groups for the primary
end point of time to onset of diabetes were
determined by the log-rank test (SAS
PROC LIFETEST; SAS/STAT version 8). If
significant, hazard ratios were deter-
mined as an estimate of relative risk of
developing diabetes. The hazard ratio was
derived using SAS PROC PHREG (Pro-
portional Hazards Regression Methods;
SAS/STAT version 8) with stratification
factors of baseline glucose tolerance (IGT
or NGT) and sex. To determine the effect
of age and BMI on the relative risk of de-
veloping type 2 diabetes, age and BMI
subgroups were categorized at baseline as
above or below the median.
Quantitative changes in primary and
secondary efficacy parameters were ana-
lyzed at yearly time points using an AN-
COVA model. This included change from
baseline as the response variable and cen-
ter, treatment, and center-by-treatment
interaction as the independent variables.
Baseline values were used as covariates.
For lipid parameters, the response vari-
able was percentage change. We also an-
alyzed body weight changes categorically.
Descriptive statistics for all secondary pa-
rameters involving changes over time
used observed data. Descriptive statistics
 Torgerson and Associates

Table 1—Demographic and clinical characteristics of the study participants at baseline ITT mature discontinuation were refusal of
population treatment (14 and 20%, respectively) and
insufficient therapeutic response (8 and
Placebo ⫹ lifestyle Orlistat ⫹ lifestyle 19%, respectively).
Baseline data were compared be-
n 1,637 1,640 tween completers and noncompleters.
Sex (n [%]) There was no substantial difference at
Female 905 (55.3) 905 (55.2) baseline in age, weight, BMI, or the male-
Male 732 (44.7) 735 (44.8) to-female ratio between completers and
Age (years) 43.7 ⫾ 8.0 43.0 ⫾ 8.0 noncompleters in either treatment group
Weight (kg) 110.6 ⫾ 16.5 110.4 ⫾ 16.3 (data not shown).
BMI (kg/m2) 37.4 ⫾ 4.5 37.3 ⫾ 4.2
Waist circumference (cm) 115.4 ⫾ 10.4 115.0 ⫾ 10.4 Adherence
IGT patients (n [%]) 344 (21) 350 (21.3) For the ITT population, the actual calorie
Whole blood glucose deficit over the 4 study years was similar
Fasting (mmol/l) 4.6 ⫾ 0.6 4.6 ⫾ 0.6 to the prescribed 800 kcal/day deficit:
2 h (mmol/l) 5.5 ⫾ 1.6 5.5 ⫾ 1.6 ⫺673 ⫾ 825 kcal/day in orlistat-treated
AUC (mmol 䡠 min⫺1 䡠 l⫺1) 799 ⫾ 179 804 ⫾ 175 patients and ⫺744 ⫾ 935 kcal/day in pla-
Serum insulin cebo-treated patients. Orlistat- and
Fasting (pmol/l) 83.6 ⫾ 47.2 86.1 ⫾ 50.1 placebo-treated patients walked similar
2 h (pmol/l) 344.9 ⫾ 298.5 370.9 ⫾ 336.7 additional distances over the 4 years
AUC (nmol 䡠 min⫺1 䡠 l⫺1) 47.7 ⫾ 28.4 49.7 ⫾ 31.3 (mean ⫾ SD: an extra 9.5 ⫾ 6.6 and
Diastolic BP (mmHg) 82.3 ⫾ 10.0 82.0 ⫾ 10.0 9.9 ⫾ 8.3 km/week, respectively).
Systolic BP (mmHg) 130.4 ⫾ 15.4 130.8 ⫾ 15.8 Average compliance with study drug
Total cholesterol (mmol/l) 5.8 ⫾ 1.0 5.8 ⫾ 1.0 administration from first dose until treat-
LDL cholesterol (mmol/l) 3.8 ⫾ 0.9 3.7 ⫾ 0.9 ment termination was 93.3% for orlistat
HDL cholesterol (mmol/l) 1.2 ⫾ 0.3 1.2 ⫾ 0.3 patients and 92.8% for placebo patients.
LDL-to-HDL ratio 3.3 ⫾ 1.0 3.2 ⫾ 1.1 This difference was not statistically
Triglycerides (mmol/l) 1.9 ⫾ 1.2 1.9 ⫾ 1.0 significant.
Fibrinogen (␮mol/l) 11.7 ⫾ 2.0 11.7 ⫾ 2.2
Plasminogen activator inhibitor-1 (U/ml) 22.9 ⫾ 10.0 23.1 ⫾ 10.0 Primary efficacy parameters
Energy intake (kcal/day) 2,927 ⫾ 1,148 2,909 ⫾ 1,030 Incidence of type 2 diabetes. During 4
Data are means ⫾ SD, unless otherwise noted. AUC, area under the curve, BP, blood pressure. years of treatment, orlistat plus lifestyle
changes significantly decreased the pro-
gression to type 2 diabetes compared with
for change in body weight and categorical [52%] vs. 564 of 1,655 [34%]; P ⬍ placebo plus lifestyle changes (log-rank
body weight changes used last observa- 0.0001). For both the orlistat and placebo P ⫽ 0.0032). Cumulative incidence rates
tion carried forward (LOCF) data unless groups, the most common causes of pre- after 4 years were 6.2 vs. 9.0% (Fig. 1).
otherwise noted. Observed, LOCF, and
baseline observation carried forward
(BLCF) (13) methods were used for hy-
pothesis testing of quantitative parameters.

RESULTS — From August to Decem-

ber 1997, 3,305 study participants were
randomized to treatment with orlistat
plus lifestyle changes (n ⫽ 1,650) or pla-
cebo plus lifestyle changes (n ⫽ 1,655), of
which 3,304 were treated. The last 4-year
examination was completed in February
2002. The ITT population comprised
1,640 (orlistat group) and 1,637 (placebo
group) patients. The baseline demo-
graphic and clinical characteristics of the
two treatment groups were similar (Table
1). The safety population comprised
1,649 and 1,655 patients, respectively. A Figure 1—Cumulative incidence of diabetes by study group in all obese patients (IGT or NGT at
greater number of orlistat-treated patients baseline) and only in obese patients with IGT at baseline. The decrease in the risk of developing
completed treatment compared with pla- diabetes with orlistat plus lifestyle compared with placebo plus lifestyle is indicated. P values
cebo-treated patients (850 of 1,650 shown are for the log-rank test.

DIABETES CARE, VOLUME 27, NUMBER 1, JANUARY 2004 157

Orlistat and diabetes prevention
Figure 2—Weight loss (means ⫾ SEM) during 4 years of treatment with orlistat plus lifestyle
changes or placebo plus lifestyle changes in obese patients (LOCF data).
The hazard ratio (0.627 [95% CI 0.455–
0.863]) corresponds to a 37.3% decrease
in the risk of developing diabetes with or-
listat compared with placebo.
Weight change. Mean weight loss was
significantly greater with orlistat than pla-
cebo at 1 year (10.6 vs. 6.2 kg; P ⬍ 0.001)
and remained significantly greater at the
end of the 4-year study (5.8 vs. 3.0 kg;
P ⬍ 0.001) (Fig. 2). The least-square
mean difference between orlistat and pla-
cebo groups after 4 years of treatment was
⫺2.7 kg (P ⬍ 0.001) by LOCF analysis. A
second analysis in which the baseline
weights of subjects who dropped out of
the study was carried forward (i.e., as-
suming these subjects lost no weight) also
demonstrated greater weight loss in the
orlistat group (3.6 vs. 1.4 kg; P ⬍ 0.001).
For those patients who completed 4 years
of treatment (52% of the orlistat patients
and 34% of the placebo patients initially
randomized), weight loss was signifi-
cantly greater with orlistat than placebo at
year 1 (11.4 vs. 7.5 kg; P ⬍ 0.001) and
year 4 (6.9 vs. 4.1 kg; P ⬍ 0.001).
Significantly more orlistat patients
(72.8%) than placebo patients (45.1%)
achieved weight loss ⱖ5% after 1 year of
treatment (P ⬍ 0.001). A similar signifi-
cant difference was apparent for patients
achieving a weight loss ⱖ10% (41.0%
with orlistat vs. 20.8% with placebo; P ⬍
0.001). For those patients who completed
4 full years of treatment, 52.8 and 37.3%,
respectively, lost ⱖ5% of baseline body
weight (P ⬍ 0.001) and 26.2 and 15.6%,
respectively, lost ⱖ10% of baseline body
weight (P ⬍ 0.001).
Exploratory analyses. The cumulative
incidence of type 2 diabetes diagnosed on
the basis of a repeat positive test was sig-
158
nificantly lower with orlistat plus lifestyle
treatment (log-rank P ⫽ 0.028). The cu-
mulative incidence rate of type 2 diabetes
after 4 years was 2.9% with orlistat versus
4.2% for placebo, corresponding to a
41% risk reduction (hazard ratio 0.593).
In patients with IGT at baseline, orl-
istat plus lifestyle changes significantly
decreased the progression to type 2 dia-
betes when diagnosed on the basis of a
single test (log-rank P ⫽ 0.0024). Cumu-
lative incidence rates after 4 years were
18.8 vs. 28.8% (Fig. 1), corresponding to
a 45% risk reduction (hazard ratio
0.551). In addition, orlistat plus lifestyle
changes significantly decreased the pro-
gression to type 2 diabetes when diag-
nosed by repeat positive testing in this
subgroup with IGT (log-rank P ⫽
0.0171). Cumulative incidence rates after
4 years were 8.3% with orlistat versus
14.2% with placebo, corresponding to a
52% risk reduction (hazard ratio 0.482).
In patients with NGT at baseline, the
progression rate to type 2 diabetes with
placebo was very low (2.7% over 4 years)
and insufficient to detect a statistically sig-
nificant difference compared with orlistat
(2.6% over 4 years).
Table 2—The effect of baseline strata on the relative risk of developing type 2 diabetes over 4
years in patients, irrespective of treatment
Variable
Treatment group: orlistat versus placebo
Glucose tolerance: impaired versus normal
Sex: male versus female
Age (years): ⬎44* vs. ⱕ44
BMI (kg/m2): ⱖ37 vs. ⬍37*
*Median.
DIABETES CARE, VOLUME 27, NUMBER 1, JANUARY 2004
Independent of orlistat or placebo
treatment, the relative risk of developing
type 2 diabetes was greater in patients
with IGT than in those with NGT, in men
than in women, in older than in younger
individuals, and in individuals with a
higher BMI (Table 2). Weight loss was sig-
nificantly greater with orlistat than pla-
cebo in both patients with IGT at baseline
(5.7 kg with orlistat vs. 3.0 kg with pla-
cebo; P ⬍ 0.01) and patients with NGT
(5.8 vs. 3.0 kg, respectively; P ⬍ 0.001).
Secondary efficacy parameters
Treatment with orlistat plus lifestyle
changes resulted in early and significant
improvements in cardiovascular risk fac-
tors that were sustained throughout the
study, including blood pressure, waist
circumference, and lipids (Table 3). Total
and LDL cholesterol and the LDL-to-HDL
cholesterol ratio decreased significantly
more with orlistat than placebo, at both 1
and 4 years. Consistent with this, HDL
cholesterol increased less with orlistat.
There was no difference in the pro-
gression rate from NGT to IGT over 4
years between orlistat- and placebo-
treated individuals (27.6 vs. 30.5%, P ⫽
0.1521).
Safety
Orlistat was well tolerated during the
study. The overall incidence of adverse
events was similar in the two treatment
groups, with the exception of a higher in-
cidence of gastrointestinal events. Most
gastrointestinal events were mild to mod-
erate in intensity and occurred during the
early phase of treatment. During the first
year of treatment, the proportion of pa-
tients experiencing at least one gastroin-
testinal event with orlistat or placebo was
91 vs. 65%, respectively. This compares
with 36 vs. 23% for orlistat or placebo,
respectively, during the 4th year.
Over the 4-year period, a similar pro-
Hazard ratio 95% CI P
0.63 (0.46–0.87) 0.0052
10.60 (7.30–15.40) ⬍0.0001
1.41 (1.02–1.96) 0.0390
1.44 (1.02–2.04) 0.0383
1.36 (0.97–1.91) 0.0726
 Torgerson and Associates

Table 3—Mean change from baseline of cardiovascular risk factors at years 1 and 4 in all patients (observed data)

Year 1 Year 4
Placebo ⫹ Orlistat ⫹ P between Placebo ⫹ Orlistat ⫹ P between
lifestyle lifestyle treatments* lifestyle lifestyle treatments*
n 1,295 1,487 567 851
Diastolic BP (mmHg) ⫺2.6 ⫺3.6 ⬍0.01 ⫺1.9 ⫺2.6 ⬍0.01
Systolic BP (mmHg) ⫺5.2 ⫺7.3 ⬍0.01 ⫺3.4 ⫺4.9 ⬍0.01
Total cholesterol (%) ⫺1.3 ⫺8.8 ⬍0.01 ⫺2.3 ⫺7.9 ⬍0.01
LDL cholesterol (%) ⫺1.6 ⫺11.4 ⬍0.01 ⫺5.1 ⫺12.8 ⬍0.01
HDL cholesterol (%) 8.5 3.4 ⬍0.01 9.1 6.5 ⬍0.01†
LDL-to-HDL ratio ⫺0.3 ⫺0.5 ⬍0.01 ⫺0.4 ⫺0.6 ⬍0.01
Triglycerides (%) ⫺6.3 ⫺6.2 ⬍0.05‡ 2.9 2.4 NS
Waist circumference (cm) ⫺7.0 ⫺9.6 ⬍0.01 ⫺4.4 ⫺6.4 ⬍0.01
Venous whole blood glucose (mmol/l)
Fasting 0.2 0.1 ⬍0.01§ 0.2 0.1 ⬍0.01㛳
2h ⫺0.4 ⫺0.6 ⬍0.01 ⫺0.2 ⫺0.4 ⬍0.01¶
AUC (mmol 䡠 min⫺1 䡠 l⫺1)# ⫺27 ⫺51 ⬍0.01 3 ⫺14 ⬍0.01
Serum insulin (pmol/l)
Fasting ⫺17.0 ⫺26.5 ⬍0.01 ⫺20.6 ⫺32.0 ⬍0.01
2h ⫺107.5 ⫺157.4 ⬍0.01 ⫺76.7 ⫺115.4 ⬍0.01¶
AUC (nmol 䡠 min⫺1 䡠 l⫺1)# ⫺11.0 ⫺14.6 ⬍0.01 ⫺8.4 ⫺10.9 ⬍0.01
Fibrinogen (␮mol/l) 0.1 0.2 NS ⫺0.5 ⫺0.4 ⬍0.05㛳
Plasminogen activator inhibitor-1 (U/ml) ⫺3.0 ⫺7.1 ⬍0.01 0.1 ⫺3.0 ⬍0.01
*P values apply to analyses by LOCF ITT, BLCF ITT, and observed data, except where indicated; †LOCF and BLCF ⫽ NS; ‡LOCF and observed ⫽ NS; §BLCF P ⬍
0.05; 储BLCF ⫽ NS; ¶observed ⫽ NS; #calculated by trapezoid rule, including all areas above the line y ⫽ 0, from measurements immediately before and 30, 60, 90,
and 120 min after dose. AUC, area under the curve; BP, blood pressure.

portion of placebo-treated patients had at
least one serious adverse event as com-
pared with orlistat-treated patients (13 vs.
15%). Similar proportions of serious gas-
trointestinal events occurred in the pla-
cebo (n ⫽ 32; 2%) and orlistat (n ⫽ 32;
2%) groups. No deaths were attributed to
study medication. Overall, 4% of placebo
patients and 8% of orlistat patients with-
drew from the study because of adverse
events or laboratory abnormalities; the
difference was primarily due to gastroin-
testinal events.
There were statistically significant de-
creases in the orlistat group compared
with the placebo group after 4 years of
treatment for all assessed fat-soluble vita-
mins (vitamin A ⫺0.22 vs. ⫺0.19 ␮mol/l,
P ⬍ 0.05; 25-hydroxyvitamin D ⫺17.2
vs. ⫺13.0 nmol/ml, P ⬍ 0.001; vitamin E
⫺2.8 vs. 0.4 ␮mol/l, P ⬍ 0.001; and vi-
tamin K1 ⫺0.08 vs. 0.07 ␮g/l, P ⬍ 0.001),
with the exception of 1,25-hydroxyvita-
min D (⫺15.8 vs. ⫺14.0 pmol/ml). How-
ever, the mean level of each assessed
vitamin remained well within its refer-
ence range at all times during the 4-year
study for both the orlistat and placebo
groups. Decreases were seen early and
then were maintained over the treatment
period. In patients with normal baseline
vitamin levels, the proportions with two
subsequent, consecutive abnormally low
values was similar in the orlistat and pla-
cebo groups for vitamin A (5.5 vs. 4.4%,
respectively) and notably different only
for vitamin E (3.2 vs. 0.5%, respectively).
Proportions for all other vitamin levels
were ⬍1% and similar between treatment
groups.
CONCLUSIONS — XENDOS was a
4-year, prospective, randomized, double-
blind, placebo-controlled study con-
ducted in a representative cohort of obese
patients with NGT or IGT. The study
demonstrated that orlistat plus lifestyle
changes significantly reduced the inci-
dence of type 2 diabetes over 4 years and
improved weight loss when compared
with placebo plus lifestyle changes. The
overall effect of orlistat in preventing dia-
betes in our study population was primar-
ily due to the beneficial effect in IGT
patients. Because the cumulative inci-
dence of diabetes in patients with baseline
NGT was low, no between-treatment dif-
ference was discernable in this subgroup.
Furthermore, cardiovascular risk factors
were improved with orlistat treatment,
with sustained and significantly better im-
provements than with placebo for most
measures. The XENDOS study has also
demonstrated the long-term safety of orl-
istat. The adverse events profile for orl-
istat in this 4-year study was consistent
with that observed in previous 2-year
studies (14 –16).
The XENDOS study represents a fur-
ther step forward in the evolution of dia-
betes preventive studies. In contrast to
other prevention studies, both groups in
XENDOS were prescribed intensive life-
style changes in addition to receiving ei-
ther a placebo or an active treatment, in
this case the weight-reducing agent orl-
istat. Early studies that were not fully con-
trolled indicated that lifestyle change
might reduce the incidence of diabetes in
obese individuals with IGT (17,18). The
beneficial effects of intensive lifestyle
changes (compared with standard care) in
preventing diabetes in individuals with
IGT were later demonstrated in the DPS
(7) and DPP (8). In parallel, the DPP (8),
the Study to Prevent (STOP)-NIDDM
(19), and the Troglitazone in the Preven-
tion of Diabetes (TRIPOD) (20) trials
demonstrated that antidiabetic drugs
were similarly more effective than stan-

DIABETES CARE, VOLUME 27, NUMBER 1, JANUARY 2004 159

Orlistat and diabetes prevention
dard care alone. However, in the study
with an intensive lifestyle group (8), drug
treatment was less effective. In the current
study, the placebo group was treated with
lifestyle changes and lost a meaningful
amount of weight over the 4 years; adding
orlistat to lifestyle changes produced
more weight loss and led to a significantly
lower risk of developing type 2 diabetes.
Our results indicated that patients
treated with placebo plus lifestyle changes
achieved a weight loss of 3.0 kg over 4
years, which is comparable with that in
the intensive lifestyle intervention arms of
the DPS (3.5 kg) (7) and DPP (3.5 kg) (8).
The addition of orlistat to lifestyle
changes resulted in a significantly greater
weight loss, which was similar among
patients with IGT and patients with NGT
at baseline. Therefore, XENDOS has
demonstrated for the first time that a
weight loss agent in combination with
lifestyle changes over 4 years is of greater
benefit than lifestyle changes alone for
producing long-term weight loss and im-
provements in cardiovascular risk factors.
The difference in weight loss between or-
listat- and placebo-treated patients was
similar whether assessed by LOCF or
BLCF analysis.
The cumulative incidence of repeat
positive diabetes in the XENDOS placebo
plus lifestyle group for our baseline IGT
subjects (14.2%) was of a similar magni-
tude to that of the intensive intervention
groups in the comparable DPS and DPP
studies (11–14.4%) (7,8). The addition of
orlistat to lifestyle changes in XENDOS
reduced the incidence of type 2 diabetes
in subjects with IGT by 52% when com-
pared with the placebo and lifestyle
group. Although comparisons between
studies should be done with caution, the
risk reduction for orlistat plus lifestyle
changes compared with standard care
may be substantial.
In the IGT population, using the cu-
mulative incidence rates provided, our re-
sults suggest that treating 10 patients with
orlistat plus lifestyle (rather than lifestyle
alone) for 4 years would prevent the de-
velopment of one case of diabetes.
It should be noted that our study was
powered to detect differences in progres-
sion to type 2 diabetes in the overall co-
hort, which was a clinically representative
population of obese subjects having ei-
ther NGT or IGT. Because of the high pro-
portion of emergent cases in subjects with
IGT at baseline, significant exploratory re-
160
sults were obtained from this subgroup.
However, the study was not powered to
detect treatment differences in the sub-
group with NGT at baseline, for which the
progression rate to type 2 diabetes turned
out to be very low.
One consideration in long-term
weight loss studies is the proportion of
patients who discontinue prematurely. In
our study, retention rates of 52% with or-
listat and 34% with placebo after 4 years
were not unexpected in view of previous
obesity studies with up to 2 years’ dura-
tion (14,15,21,22). Overall, there were
fewer withdrawals with orlistat, possibly
due to the greater weight loss in this
group. Withdrawals due to insufficient
response were more than twice as fre-
quent in the placebo group compared
with that of the orlistat group. Because of
the event-based study design, the discon-
tinuation rate did not affect the power of
the study.
One limitation of XENDOS was that
repeat testing of patients with a positive
OGTT result was not instituted until the
majority of patients had completed the
6-month examination. Therefore some
repeat positive tests were not captured.
However, 87% of all cases of type 2 dia-
betes were diagnosed after the 6-month
time point, at which the second OGTT
was introduced. Analyses using only
those patients with data available from a
repeat positive test show similar results
compared with the results from only one
positive test.
In summary, the addition of orlistat to
lifestyle changes significantly reduces the
incidence of type 2 diabetes in obese sub-
jects. With our study design, reduction
was only apparent in the IGT subgroup.
Adding orlistat also significantly increases
weight loss in obese patients with either
IGT or NGT and improves other cardio-
vascular risk factors. Orlistat treatment is
safe and well tolerated over 4 years of
treatment.
Acknowledgments — This study was sup-
ported by F. Hoffmann-La Roche.
We would like to thank the following inves-
tigators for their contributions to this study:
Krister Arlinger, Marcus Käppi, Ulf Adamsson,
Bo Berger, Jens Börretzen, Kerstin Broström,
Jan Carlström, Viveca Engblom, Jan Eriksson,
Per Gyllén, Stefan Håkansson, Peter Hallgren,
Thomas Kjellström, Ibe Lager, Mona Landin-
Olsson, Owe Larsson, Ulrik Mathiesen, Bengt
Möller, Peter Nicol, Per-Olof Olsson, Mats
DIABETES CARE, VOLUME 27, NUMBER 1, JANUARY 2004
Palmér, Bengt Petterson, Stephan Rössner,
Gunnar Strömblad, Karl-Axel Svensson, Rachel
Tengel, Bengt Vessby, Olov Wålinder, and Ro-
salind Wilson.
This work was presented at the 9th Interna-
tional Congress of Obesity in São Paolo, Brazil,
24 –29 August 2002.
References
1. World Health Organization: Controlling
the global obesity epidemic [article on-
line], 2002. Available from http://www.
who.int/nut/obs.htm. Accessed 26 March
2003
2. Colditz GA, Willett WC, Rotnitzky A,
Manson JE: Weight gain as a risk factor for
clinical diabetes mellitus in women. Ann
Intern Med 122:481– 486, 1995
3. Must A, Spadano J, Coakley EH, Field AE,
Colditz G, Dietz WH: The disease burden
associated with overweight and obesity.
JAMA 282:1523–1529, 1999
4. Hu FB, Manson JE, Stampfer MJ, Colditz
G, Liu S, Solomon CG, Willett WC: Diet,
lifestyle, and the risk of type 2 diabetes
mellitus in women. N Engl J Med 345:
790 –797, 2001
5. Kumanyika S, Jeffery RW, Morabia A,
Ritenbaugh C, Antipatis VJ: Obesity pre-
vention: the case for action. Int J Obes Relat
Metab Disord 26:425– 436, 2002
6. Sjöström CD, Peltonen M, Wedel H, Sjös-
tröm L: Differentiated long-term effects
of intentional weight loss on diabetes
and hypertension. Hypertension 36:20 –25,
2000
7. Tuomilehto J, Lindström J, Eriksson JG,
Valle TT, Hamalainen H, Ilanne-Parikka
P, Keinanen-Klukaanniemi S, Laakso M,
Louheranta A, Rastas M, Salminen V,
Uusitupa M: Prevention of type 2 diabetes
mellitus by changes in lifestyle among
subjects with impaired glucose tolerance.
N Engl J Med 344:1343–1350, 2001
8. Knowler WC, Barrett-Connor E, Fowler
SE, Hamman RF, Lachin JM, Walker EA,
Nathan DM, Diabetes Prevention Pro-
gram Research Group: Reduction in the
incidence of type 2 diabetes with lifestyle
intervention or metformin. N Engl J Med
346:393– 403, 2002
9. Heymsfield SB, Segal KR, Hauptman J,
Lucas CP, Boldrin MN, Rissanen A, Wild-
ing JP, Sjöström L: Effects of weight loss
with orlistat on glucose tolerance and pro-
gression to type 2 diabetes in obese adults.
Arch Intern Med 160:1321–1326, 2000
10. Torgerson JS, Arlinger K, Käppi M, Sjös-
tröm L: Principles for enhanced recruit-
ment of subjects in a large clinical trial:
the XENDOS (XENical in the prevention
of Diabetes in Obese Subjects) study ex-
perience. Control Clin Trials 22:515–525,
2001
11. World Health Organization: Prevention of

Diabetes Mellitus. Geneva, World Health
Org., 1994, p. 17–18 (Tech. Rep. Ser., no.
844)
12. Lindroos AK, Lissner L, Sjöström L: Va-
lidity and reproducibility of a self-admin-
istered dietary questionnaire in obese and
non-obese subjects. Eur J Clin Nutr 47:
461– 481, 1993
13. Ware JH: Interpreting incomplete data in
studies of diet and weight loss. N Engl
J Med 348:2136 –2137, 2003
14. Sjöström L, Rissanen A, Andersen T,
Boldrin M, Golay A, Koppeschaar HP,
Krempf M: Randomised placebo-con-
trolled trial of orlistat for weight loss and
prevention of weight regain in obese pa-
tients. Lancet 352:167–172, 1998
15. Davidson MH, Hauptman J, DiGirolamo
M, Foreyt JP, Halsted CH, Heber D,
Heimburger DC, Lucas CP, Robbins DC,
Chung J, Heymsfield SB: Weight control
and risk factor reduction in obese subjects
treated for 2 years with orlistat: a random-
DIABETES CARE, VOLUME 27, NUMBER 1, JANUARY 2004
ized controlled trial. JAMA 281:235–242,
1999
16. Rössner S, Sjöström L, Noack R, Meinders
AE, Noseda G: Weight loss, weight main-
tenance, and improved cardiovascular
risk factors after 2 years’ treatment with
orlistat for obesity: European Orlistat
Obesity Study Group. Obes Res 8:49 – 61,
2000
17. Pan XR, Li GW, Hu YH, Wang JX, Yang
WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao
HB, Liu PA, Jiang XG, Jiang YY, Wang JP,
Zheng H, Zhang H, Bennett PH, Howard
BV: Effects of diet and exercise in prevent-
ing NIDDM in people with impaired glu-
cose tolerance: the Da Qing IGT and
Diabetes Study. Diabetes Care 20:537–
544, 1997
18. Eriksson KF, Lindgärde F: Prevention of
type 2 (non-insulin-dependent) diabetes
mellitus by diet and physical exercise: the
6-year Malmö feasibility study. Diabetolo-
gia 34:891– 898, 1991
Torgerson and Associates
19. Chiasson J-L, Josse RG, Gomis R,
Hanefeld M, Karasik A, Laakso M: Acar-
bose for prevention of type 2 diabetes
mellitus: the STOP-NIDDM randomised
trial. Lancet 359:2072–2077, 2002
20. Buchanan T, Xiang AH, Peters RK, Kjos
SL, Marroquin A, Goico J, Ochoa C, Tan
S, Berkowitz K, Hodis HN, Azen SP: Pres-
ervation of pancreatic ␤-cell function and
prevention of type 2 diabetes by pharma-
cological treatment of insulin resistance in
high-risk Hispanic women. Diabetes 51:
2796 –2803, 2002
21. Safer DJ: Diet, behavior modification and
exercise: a review of obesity treatments
from a longitudinal perspective. South
Med J 84:1470 –1474, 1991
22. Glenny AM, O’Meara S, Melville A, Shel-
don TA, Wilson C: The treatment and
prevention of obesity: a systematic review
of the literature. Int J Obes Relat Metab Dis-
ord 21:715–737, 1997
161